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J Invest Dermatol. 2019 Apr;139(4):807-817. doi: 10.1016/j.jid.2018.10.024. Epub 2018 Nov 3.

Pharmacological Inhibition of Serine Palmitoyl Transferase and Sphingosine Kinase-1/-2 Inhibits Merkel Cell Carcinoma Cell Proliferation.

Author information

1
Gottfried Schatz Research Center, Division of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
2
Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria; Department of Translational Skin Cancer Research, University Hospital Essen, Essen, Germany.
3
Otto Loewi Research Center, Division of Immunology and Pathophysiology, Medical University of Graz, Graz, Austria.
4
Department of Obstetrics and Gynecology, Medical University of Graz, Graz, Austria.
5
Institute of Molecular Biosciences, University of Graz, Graz, Austria; Center for Explorative Lipidomics, BioTechMed-Graz, Graz, Austria.
6
Diagnostic and Research Center for Molecular Biomedicine, Institute of Pathology, Medical University of Graz, Graz, Austria.
7
Department of Translational Skin Cancer Research, University Hospital Essen, Essen, Germany.
8
Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
9
Department of Translational Skin Cancer Research, University Hospital Essen, Essen, Germany; German Cancer Consortium (DKTK/DKFZ), Heidelberg, Germany. Electronic address: j.becker@dkfz.de.
10
Gottfried Schatz Research Center, Division of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria; Center for Explorative Lipidomics, BioTechMed-Graz, Graz, Austria. Electronic address: wolfgang.sattler@medunigraz.at.

Abstract

The majority of Merkel cell carcinoma, a highly aggressive neuroendocrine cancer of the skin, is associated with Merkel cell polyomavirus infection. Polyomavirus binding, internalization, and infection are mediated by glycosphingolipids. Besides receptor function, bioactive sphingolipids are increasingly recognized as potent regulators of several hallmarks of cancer. Merkel cell polyomavirus+ and Merkel cell polyomavirus- cells express serine palmitoyl transferase subunits and sphingosine kinase (SK) 1/2 mRNA. Induced expression of Merkel cell polyomavirus-large tumor antigen in human lung fibroblasts resulted in upregulation of SPTLC1-3 and SK 1/2 expression. Therefore, we exploited pharmacological inhibition of sphingolipid metabolism as an option to interfere with proliferation of Merkel cell polyomavirus+ Merkel cell carcinoma cell lines. We used myriocin (a serine palmitoyl transferase antagonist) and two SK inhibitors (SKI-II and ABC294640). In MKL-1 and WaGa cells myriocin decreased cellular ceramide, sphingomyelin, and sphingosine-1-phosphate content. SKI-II increased ceramide species but decreased sphingomyelin and sphingosine-1-phosphate concentrations. Aberrant sphingolipid homeostasis was associated with reduced cell viability, increased necrosis, procaspase-3 and PARP processing, caspase-3 activity, and decreased AKTS473 phosphorylation. Myriocin and SKI-II decreased tumor size and Ki-67 staining of xenografted MKL-1 and WaGa tumors on the chorioallantoic membrane. Our data suggest that pharmacological inhibition of sphingolipid synthesis could represent a potential therapeutic approach in Merkel cell carcinoma.

PMID:
30399362
DOI:
10.1016/j.jid.2018.10.024

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